Vasoactive intestinal peptide (VIP) is one of several transmitters innervating mammalian submandibular salivary glands (SMG) and are involved in regulating saliva production and secretion, processes that are essential for proper oral hygiene and digestion. Although effects of VIP on vasodilation and saliva volume and ion content have been described in in vivo and organ preparations, the specific ion transport processes regulated by VIP receptor activation and the mechanisms through which this regulation is accomplished are unknown. VIP receptors in other tissues are positively coupled to adenylate cyclase and, at least in HT29 colon cells, the VIP receptor/adenylate cyclase system is down-regulated by prior exposure to either receptor agonists or activators of protein kinase C. Whether VIP receptors in SMG are regulated in this manner, and what the consequences of this regulation are on SMG ion transport systems are not known. Although none have been identified, a continuous, homogeneous cell line retaining characteristics of normal SMG acinar or ductal cells would be very useful in studying SMG ion transport. Therefore, in addition to assessing VIP effects on ion transport systems in perfused glands and in acini, the A-253 adenocarcinoma cell line isolated from human submaxillary gland will be evaluated as a model for studying SMG ion transport, VIP-R mediated effects on ion transport and regulation of VIP receptors. Preliminary data suggest that these cells will be useful, in that A-253 cells exhibit a VIP receptor/adenylate cyclase system that is down-regulated by agonists and ion transport systems that are blocked by Na/K ATPase and aa/K/Cl cotransport inhibitors. Using perfused glands, isolated acini and A-253 cells, three major aspects of SMG function will be addressed. These are the role of VIP receptors in regulator specific SMG ion transport processes and the mechanisms thereof; the homologous and heterologous regulation of the SMG VIP receptor/adenylate cyclase system; and the consequences of VIP receptor/adenylate cyclase regulation on SMG ion transport. The information obtained from these studies promises to provide a fuller understanding of the role of VIP in normal salivary gland function and to establish a framework in which to study lesions in neuropeptide receptor/signaling systems in diseases affecting salivary and other exocrine glands.